Parkinson

30 years fighting Parkinson's disease through Personalized Medicine and Genomics.

What is Parkinson's disease?

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, affecting between 1 and 3% of the population over 65 years of age in Western countries. It is a chronic, progressive and disabling movement disorder whose etiology or cause is currently unknown, although it is believed to have a multifactorial origin.

Parkinson's disease belongs to the group of parkinsonian syndromes, characterized in its clinical manifestations by:

Tremor
Muscle stiffness
Bradykinesia (slowness of movement) postural alterations
The disease may also be accompanied by psychiatric manifestations (visual hallucinations and depression), although these are not always present.

The lesion that gives rise to the disease is the alteration of the dopaminergic pathway between the substantia nigra and the striatal nucleus of the brain (nigrostriatal dopaminergic pathway) that causes a decrease in the neurotransmitter dopamine.

Causes and risk factors of Parkinson's disease

PD is a movement disorder characterized by tremor, rigidity and bradykinesia. These symptoms appear decades after the neuronal death process has begun.

This progressive destruction affects preferentially the dopaminergic neurons of the basal ganglia, especially the nigrostriatal pathways that are organized in the compact part of the substantia nigra. This degeneration and death of dopaminergic neurons leads to the loss of the neurotransmitter dopamine in the affected areas of the brain, and this loss is responsible for the characteristic symptoms of the disease.

In addition to this neuropathological finding, there is another very characteristic of the disease, which is the presence of Lewy bodies in dopaminergic neurons. These are abnormal accumulations of proteins, mainly alpha-synuclein, an important protein in the normal functioning of our brain, especially in neuronal synapses, through which neurons communicate. For unknown reasons, alpha-synuclein loses its original structure (the functions of proteins are determined by their structure, something like a building) and accumulates forming Lewy bodies.

Among the main risk factors for developing Parkinson's disease is age, since it has been shown to be the most important factor in the development of the disease, with an average onset of approximately 50 to 60 years of age.

Other importantother important risk factors are:

Family history
Continued exposure to environmental neurotoxic agents, drugs, pesticides, pesticides, etc., is a major risk factor.
Traumatic microinjuries
Cerebral microinfarcts
Oxidative processes that enhance free radical formation and failure of anti-oxidative systems.
Endogenous or reactive neuroimmune and neuroinflammatory reactions that damage dopaminergic neurons.
Dysfunction of the ubiquitin-proteasome system, unable to adequately process proteins whose conformational changes turn them into endogenous neurotoxicity elements.
Genomic defects in several genes distributed throughout the human genome.
Epigenetic changes (DNA methylation, chromatin alterations, dysfunction of microRNAs).

It is highly probable, as with other neurodegenerative diseases, that the confluence of genomic vulnerability factors, with epigenetic changes, and environmental factors, is the main cause of the growing impact of Parkinson's disease in our society today.

There is clear evidence that the neurodegenerative process responsible for PD begins decades before the onset of disease symptoms, so that by the time the motor impairment of PD begins, billions of dopaminergic neurons have already died, and neuro-regeneration is currently impossible.

Therefore, future treatments should be aimed both at protecting dopaminergic neurons from dying and at mitigating the psychomotor component that accompanies dopaminergic neurodegeneration.

Age

Age is a clear risk factor, with the average age of onset being between 55-60 years. Thus, the prevalence increases exponentially from the sixth decade of life, from 41 cases per 100,000 in the fourth decade of life to more than 1,900 cases per 100,000 in people over 80 years of age. When PD appears before the age of 50, it is called Early Onset PD.

Genomic Factors

Numerous scientific papers have shown a higher frequency of Parkinson's disease cases among relatives of an affected person compared to those with no family history of the disease. The level of genetic contribution in Parkinson's appears to be determined by the age of onset of the disease, the earlier the onset of the disease, the greater the chance of having a family member affected.

The genetic component associated with familial forms of the disease corresponds to approximately 10%, while the remaining 90% are classified as sporadic, apparently non-familial cases.

It is believed that more than half a thousand genes could be involved in PD; of which, about 18 loci (PARK1-18) distributed throughout the human genome are pathogenic and potentially causative of heritable forms of PD (a-synuclein, LRRK2, Parkin, PINK1, DJ-1, ATP13A2), while other loci (e.g. LRRK2, MAPT, SCA1, SCA2, spatacsin, POLG1, GBA) appear to be more genetic susceptibility or vulnerability elements, associated with apparently sporadic forms of PD, whose familial component is undeniable, despite their supposed sporadicity.

All these genes are under the influence of epigenetic machinery that regulates their expression in different tissues and may contribute to the selective neurodegeneration of dopaminergic neurons in the substantia nigra.

A recent study has established population patterns of high susceptibility to pesticides based on the genomic profile of individuals, with special emphasis on genes responsible for pesticide metabolism (PON1), transporter genes that regulate the passage of xenobiotic agents across the blood-brain barrier (ABCB1), dopamine transporter genes (DAT/SLC6A3) or regulators of its metabolism (ALDH2), genes that influence mitochondrial oxidative/nitrosative function (NOS1), proteasome inhibitors (SKP1), or immune function regulators (HLA-DR).

Parkinson's disease is a genetically complex disease produced by the interaction of multiple environmental factors and variations in different genes. These genetic variants determine susceptibility or resistance to the disease and response to treatment.

Due to the interaction between genes and environment, complex diseases can be prevented by acting on environmental factors with an appropriate prevention plan.

A person's chance of developing Parkinson's is greater when there is a family history of the disease.

At EuroEspes we have designed a genetic risk panel for 22 DNA markers related to Parkinson's disease where the patient's risk profile is defined as the carrier status of risk variants. This tool contributes to a better understanding by the physician of the patient's individual characteristics in terms of symptoms, responsiveness to treatment and helps him to decide on the best way to approach the problem in a personalized way.

Symptoms and clinical picture of Parkinson's disease

The clinical picture of PD is highly heterogeneous. Understanding the factors that determine disease progression in individual patients could have important implications for prognosis, clinical trial design, and future strategies for individualized therapy. A substantial component of Parkinson's risk is heritable, suggesting that genetic variability may also affect the clinical phenotype once the disease manifests.

Parkison's disease is characterized by the selective loss of dopaminergic neurons, resulting in motor and cognitive disturbances, including:

Tremor, these are slow and rhythmic movements. They predominate at rest and decrease when making a voluntary movement.
Muscle stiffness, muscle tension and difficulty in relaxation.
Bradykinesia, slowness of voluntary and automatic movements. This implies that simple tasks are difficult and take more time. Steps may be shorter during walking. It may be difficult to get up from a chair. There may be shuffling of the feet while walking.
Postural and balance abnormalities, inclination of the trunk and head forward. Elbows and knees are as if cramped.
Loss of automatic movements, reduced ability to perform unconscious movements, such as blinking, smiling or swinging arms during walking.
Speech changes, speaking softly, more monotone.
Changes in facial expression, loss of expressiveness.
Changes in handwriting, difficulty in writing.
Sleep disorders, loss of normal atonia during REM sleep.
Ocular symptoms: loss of visual acuity, saccadic movements (rapid eye movements), dry eyes, double vision, lack of focus, presence of visual hallucinations, among others.
Difficulties in eating, chewing and swallowing.
Alteration of the sense of smell (anosmia).
Symptoms of autonomic dysfunction (constipation, sweating disorders, sexual dysfunction, seborrheic dermatitis, urinary incontinence).
General feeling of weakness, malaise or tiredness.
Depression or anhedonia (lack of reactivity to usually pleasurable stimuli).
Slowness in thinking, diminished intellectual capacity.
Muscle and joint pain.

In many cases, Parkinson's disease coexists with depression; in more than 50% it is associated with anxiety problems; and over the years, as a result of organic wear and tear or personal predisposition, it can evolve into dementia of the dementia-Parkinson's complex type or other forms of dementia. To this must be added many other age-related complications, which are superimposed on the disability caused by Parkinson's disease itself.

Diagnosis

A study carried out by the Spanish Parkinson Federation shows that more than half of the people with Parkinson's disease in Spain take an average of between 1 and 5 years from the first symptom of the disease until they are diagnosed. In fact, 19% wait more than 5 years to receive a definitive diagnosis. During that time, people with Parkinson's and their caregivers make a fruitless journey from consultation to consultation until the diagnosis is made. Currently, the diagnosis of patients with Parkinson's disease is based mainly on clinical observation of symptoms and is supported by a series of imaging tests. Because of this, the diagnosis of these patients usually occurs when the patient is already at a more or less advanced stage of the disease, when therapeutic opportunities are already limited.

A good PD diagnosis should be based on a protocol that includes:

Anamnesis, examination and neuropsychiatric clinical examination.
Blood and urine tests .
Psychometric evaluation.
Static and functional neuroimaging radiological tests.
Cerebral and cerebrovascular function tests.
Genetic testing and pharmacogenetic profile. Identification of possible genomic alterations in genes associated with familial PD, or presence of susceptibility genes. It is also very important to know the pharmacogenetic profile of the patient to know the response to treatment.

At present, there is no biological marker to diagnose Parkinson's disease with certainty and speed. There is no value in a blood test or a physiological test to confirm it. It is a clinical diagnosis, i.e., based on the clinical history, the physical and neurological examination of the person and the presence of certain symptoms or the absence of others. The latest advances in diagnosis such as functional imaging tests, neuropsychological tests, among others, can help in the diagnosis from a suspicion based on the clinical evaluation of the symptoms and signs presented by the patient. In families in which there is hereditary Parkinson's disease attributable to a mutation of one of the genes responsible for this disease, the demonstration of this mutation in a given member can allow identification as a carrier of the disease and, if he/she presents compatible symptoms, as a person with Parkinson's disease.

There is currently no biological marker, blood test value or physiological test to confirm this.

The identification of biomarkers for the diagnosis and follow-up of these patients is therefore of great importance. The identification and validation of these biomarkers would help both in diagnosis and in the choice of the ideal treatment (precision or personalized medicine) and in monitoring the patient's response to the treatment provided.

The main objective is to find biomarkers for early diagnosis, which will make it possible to identify the risk of this disease 10 years before suffering it, thus allowing early diagnosis and treatment, thus greatly improving the patient's quality of life.

Treatments and therapies

The unsatisfactory effects of conventional antiparkinsonian drugs have prompted the search for new therapeutic alternatives.

Conventional treatments

Classical treatments for Parkinson's disease include pharmacotherapy, deep brain stimulation and physiotherapy. Conventional pharmacological treatmentsThe following products, aimed at mitigating motor symptomatology, are represented:

L-DOPA (levodopa). Precursor of dopamine synthesis. From a therapeutic perspective, the introduction of levodopa (L-DOPA) in 1960 represented a breakthrough in the treatment of PD, and it remains the most effective symptomatic therapy in parkinsonian disorders. However, chronic administration of L-DOPA and other antiparkinsonian drugs causes serious side effects that deserve special attention by the medical community. In this regard, new compounds devoid of psychomotor, biochemical, neuropsychiatric and autonomic complications are under experimental scrutiny in preclinical studies and clinical trials.
Dopaminergic agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine). They are useful in monotherapy in early stages of the disease or associated with levodopa, since they have less risk of developing motor complications than the latter.
Monoamine oxidase inhibitors, MAOIs (selegiline, rasagiline).
Catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). These are drugs that reduce the metabolism of levodopa, thus increasing its half-life and therapeutic effects, reducing its requirements by up to 30%.

One of the most relevant complications of chronic treatment with L-DOPA and other dopaminergic agents is the "wearing-off" phenomenon, characterized by motor fluctuations and dyskinesia.

To circumvent this problem, complementary strategies have been developed with dopaminergic and non-dopaminergic agents, such as new formulations of L-DOPA, COMT inhibitors (opicapone), dopaminergic agonists, A2A adenosine antagonists (istradephylline, preladenant, tozadenant), glutamatergic antangonists (NMDA, N-methyl-d-aspartate), serotonergic agents (eltoprazine), and mGluR5 glutamate receptor modulators (mavoglurant); however, none of these agents has been shown to be sufficiently effective.

Polypharmacy with antidepressants, antipsychotics, urological agents, analgesics, antihistamines and acetylcholinesterase inhibitors contribute to the development of complications, undesirable drug interactions and anticholinergic conditions. In addition, there are gastrointestinal complications (constipation, sialorrhea, dysphagia, chewing difficulties), cardiovascular problems, neuroendocrine disorders and psychiatric disorders associated with chronic use of conventional antiparkinsonian drugs.

An additional complication is Pisa syndrome, which is characterized by sustained abnormal posture with flexion of the body and head to one side and axial rotation of the trunk and is associated with the use of antipsychotics.

A bad habit in the management of psychotic symptoms in parkinsonian patients is the administration of atypical neuroleptics (such as quetiapine), which contribute to aggravate motor symptoms, due to their antidopaminergic effect, and to increase the side effects intrinsic to the antipsychotic agents themselves.

In order to administer effective medical treatment, the main objective is to provide the patient with control of signs and symptoms for as long as possible and to minimize adverse effects.

Symptomatic drug therapies usually provide some control over the motor signs of PD for the next 4-6 years of life, mainly through the use of levodopa/carbidopa as a standard symptomatic treatment prescription, while monoamine oxidase-B (MAO) inhibitor drugs may be considered more effective for treatment in the early stages of the disease.

However, other dopamine agonists (e.g. ropinirole, pramipexole) can be used as a monotherapy in early disease and as moderately effective adjuvant therapy in advanced stages of the disease. In order to minimize tremor symptoms, a second line of anticholinergic agents (e.g. trihexyphenidyl, benztropine) are also usually prescribed.

Neuroprotective treatments

Currently, the major challenges in the treatment of PD are, on the one hand, to protect dopaminergic neurons in order to prevent or halt the progression of the disease and, on the other hand, to find a treatment capable of rescuing neurons at risk of death.

The unsatisfactory effects of conventional antiparkinsonian drugs have prompted the search for new therapeutic alternatives. The use of natural substances and derived bioproducts(i.e., Vicia faba, Mucuna pruriens, Siegesbeckia pubescens, Sophora flavescens, Carthamus tinctorius, Curcuma longa, Huperzia selago, Diphasiastrum complanatum, Centella asiatica, Sulforaphane, Oleuropein, Resveratrol and other polyphenols, flavonoids, ginsenosides and caffeine) has been reactivated.

During the last decade, nutraceuticals have gained importance due to their multifaceted effects, with demonstrated activity on multiple pathways through a slow but more physiological action and without causing adverse effects. The results of several investigations support the idea that, apart from the prevention of neuronal damage, nutraceuticals can potentially attenuate the ongoing progression of neuronal destruction.

The use of nutraceuticals derived from certain plants showed, in experimental studies, that inhibit enzymes that otherwise phosphorylate protein α-synuclein, such as kinases (Cumin thymoquinone-black), casein kinase II (ellagic acid), Gprk2GRK2 / 5 or proteases such as calpains and lysosomal cysteine protease, preventing the tendency of α-synuclein to aggregate or form truncated α-synuclein toxins. Since the use of nutraceuticals presents a valid therapeutic perspective that has not yet been fully appreciated by the scientific community it is only fair to highlight the multiple properties of new plant-derived nutraceuticals.

Atremorine

E-PodoFavalin-15999 (AtreMorine®) is a novel biopharmaceutical compound obtained by non-denaturing biotechnological processes from structural components of the plant Vicia faba L.(natural source of L-dopa, precursor of the neurotransmitter dopamine), which has demonstrated a neuroprotective effect on dopaminergic neurons of the substantia nigra pars compacta (brain region affected in PD) in animal models of PD.

Clinical studies indicate that AtreMorine® is a powerful dopamine and noradrenaline enhancer in parkinsonian patients.

AtreMorine®is a good option to minimize the "wearing-off" phenomenon, prolonging the effect of conventional antiparkinsonian drugs at low doses, and, above all, to protect dopaminergic neurons against the process of premature death.

The powerful prodopaminergic effect of AtreMorine®, with a dopamine increase of 200-300 times over basal levels, is also regulated by pharmacogenetic factors, so that its therapeutic response depends on the pharmacogenetic profile of each patient. In addition to a high content of L-dopa (between 20 and 25 mg/g of AtreMorine®), AtreMorine® also contains other biologically active compounds such as phytosterols and carotenoid pigments.

Research

The priority objectives of the scientific community to combat Parkinson's disease are:

Search for reliable biomarkers to identify the risk of developing PD and to implement prophylactic programs with preventive capacity.
To optimize the therapeutic effect of available drugs by personalizing pharmacological treatment with pharmacogenetic strategies to improve efficacy and reduce toxicity.
To develop new drugs and/or bioproducts capable of protecting dopaminergic neurons against the process of premature death to which they are prone in PD.

Although the primary causes and molecular pathogenic mechanisms of PD, responsible for dopaminergic neurodegeneration, are still enigmatic, recent advances in genomic medicine (structural and functional genomics, epigenetics, transcriptomics, proteomics, metabolomics, pharmacogenomics) are allowing us to begin to understand more clearly the complex processes that lead to the alteration of the nigrostriatal dopaminergic system and consequent premature neuronal death, prototypical of the most prevalent neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

What research is being done to better understand and diagnose the disease, develop new treatments and prevent Parkinson's disease?

Biomarkers. Discover ways to identify people who are at risk of developing the disease and track disease progression. Identifying biomarkers (biological signals that may indicate risk for a disease and improve diagnosis) will accelerate the development of new therapies for PD.
Clinical studies. Current studies include genetics, biomarkers, experimental therapies and other treatment options, diagnostic imaging, brain monitoring and movement disorders, deep brain stimulation, and exercise and PD.
Animal models. They are valuable tools for scientists studying disease mechanisms to develop new treatments for people with PD. A good animal model of PD would have to exhibit some of the major features of the disease, including progressive age-dependent degeneration of vulnerable neuronal populations, intracytoplasmic inclusion formation, and motor impairment.
Genetics. Better understanding of genetic risk factors is critical to the elucidation of PD mechanisms. Current clinical research studies include the genetic connection to memory and motor behavior, the search for genes that may increase the risk of PD and related neurodegenerative disorders, and the identification of biomarkers for PD.
Environment. Risk factors such as repeated occupational exposure to certain pesticides and chemical solvents may influence the development of PD. Research is looking for environmental risk factors that increase susceptibility to developing PD before the age of 50.
Cognition and dementia. Mild cognitive impairment is common in PD, sometimes in its early stages, and some people develop dementia later in the course of the disease. Neuroimaging research studies are available to predict which people with Parkinson's might develop cognitive impairment.
Deep brain stimulation. It is considered a standard treatment option for some people with Parkinson's whose symptoms no longer respond to Parkinson's medications. Research continues to refine the optimal site within the brain to implant the deep brain stimulation electrode to help more people with the disease regain function. Researchers continue to study this intervention and develop ways to improve it.
Nerve growth factors. Studies to evaluate the effects of neurotrophic or nerve growth factors in PD.
Neuroprotective therapies. Basic, clinical and translational research to protect nerve cells from damage caused by PD.
Stem cells. Scientists are exploring various cell types, including induced pluripotent stem cells (iPSCs), as opportunities to discover drugs for PD.
Exercise. Exercise routines are often recommended to help people with PD maintain the movement and balance needed for daily life. A recent study evaluated three different forms of exercise, resistance, stretching and tai chi, and found that tai chi generally provided the greatest improvements in balance and stability for people with mild to moderate PD. A current trial is studying the effects of two levels of exercise in people who have recently been diagnosed with PD.
Mitochondrial function. The mitochondrion is a cellular organelle that is responsible for obtaining energy for cell function. Recent research has found that hundreds of genes involved in mitochondrial function are less active in people with PD.
Motor complications. The motor symptomatology of Parkinson's becomes evident as the disease progresses; these symptoms are often difficult to treat. Scientific research studies the safety and efficacy of medications and interventions to alleviate motor symptoms in people with PD.

Epidemiology

Currently, Parkinson's disease has become the second most important neurodegenerative disease in developed countries, after Alzheimer's disease, which is the neurocognitive disorder with the greatest socioeconomic and socio-health impact in industrialized countries.

The older you get, the more likely you are to suffer from Parkinson's disease, making it a serious age-related health problem.

The prevalence of Parkinson's disease ranges from 35.8 cases per 100,000 to 12,500 cases per 100,000, with an annual incidence fluctuating between 1.5 per 100,000 and 346 per 100,000 in different countries, where this disease represents a priority health problem in the adult population. A meta-analysis of data collected worldwide indicates an increase in prevalence, in parallel with age, of 41 per 100,000 between 40 and 49 years, 107 per 100,000 between 50 and 59 years, 175 per 100,000 between 55 and 64 years, 412 per 100,000 between 65 and 74 years, 1,087 per 100,000 between 70 and 79 years, and more than 1,900 per 100,000 above 80 years.

Parkinson's disease has curious geographical characteristics, with a prevalence of 1,601 cases per 100,000 in North America, Europe and Australia, and 646 cases per 100,000 in Asia. The average prevalence above the age of 65 years is 1,600 cases per 100,000; and the maximum peak prevalence is observed above the age of 90 years, with a maximum peak of 4,633 cases per 100,000.

History of Parkinson's disease

Following Dr. Parkinson' s 1817 trial of paralysis agitans, many scientists have contributed over the years to the elucidation of the substrate, causes and possible treatments of Parkinson's disease.

In 1872 Charcot would describe for the first time the cardinal symptoms of the disease, and years later he would propose the first pharmacological treatment based on belladonna alkaloids. Gowers would experiment with cannabis and opium; Barger and Ewens would synthesize dopamine; Holtz would discover the enzyme dopa decarboxylase and so on until the 1960s when L-Dopa was established as the prototypical treatment for Parkinson's disease.

Solve your doubts

If you have any queries related to Parkinson's disease

or you need more information call us at (+34) 981 780 505.

If you wish to make an appointment with our specialists, please click on the following button.